Dr. Tracy McGregor is a medical geneticist and Assistant Professor of Pediatrics at Vanderbilt University Medical Center. She has recently completed her Master of Science in Clinical Investigation, an advanced degree in patient-oriented research, and plans to pursue a career in pediatric pharmacogenetics. Her short-term goal is to develop MTRNR1 associated aminoglycoside ototoxicity as a multifaceted model of pharmacogenetics that can be incorporated into pediatric practice including assessments of parental attitudes toward pediatric pharmacogenetics. During the three years of this career development award, she plans to gain expert level knowledge in pediatric pharmacogenetics and gain research skills in qualitative methods and formal decision analysis. Her long-term goal is to conduct an independent research program as a physician scientist that brings pediatric pharmacogenetic applications into clinical practice with consideration of ethical and social implications. She proposes strong mentorship and a relevant career development plan that will enable her to successfully compete for independent funding through R01 grant mechanisms. Environment: Vanderbilt University Medical Center has identified Personalized Health and Healthcare as one of three arms in its 2005 strategic plan. Significant strides have been made, including the PREDICT program, which integrates genotyping of patients for proper clopidogrel dosing into routine clinical practice. The advances seen over the last six years have focused mainly on adult findings and applications but not pediatric initiatives. Dr. McGregor has assembled a mentorship panel who can provide her with complementary areas of expertise. Dr. Dan Roden serves as the Vice Chair for Personalized Medicine at Vanderbilt and leads the PREDICT project. Dr. Ellen Clayton, a cross-trained lawyer and pediatrician, focuses on the ethical, legal, and social implications of genetic research. Vanderbilt's Vice Chair for Pediatric Research, Dr. Louis Muglia, conducts studies in the neonatal setting to identify the genetic contributions to preterm birth. All three mentors are well-established researchers in their respective fields and have guided young investigators to successful, independent careers. With the enthusiastic support of her mentors, department, and Vanderbilt's CTSA, Dr. McGregor is well prepared to complete the training and studies in this proposal and develop into a successful academic physician scientist. Research: This proposal includes two related aims that address the emerging area of translational pediatric pharmacogenetics. Mitochondrial MTRNR1 mutations have been shown to markedly accelerate hearing loss when patients are treated with aminoglycoside antibiotics. The time course of hearing loss in patients with MTRNR1 mutations after treatment with aminoglycoside antibiotics has not been well defined, particularly in children. The first aim addresses patients with MTRNR1 mutations who have been treated with aminoglycosides and compares their incidence of hearing loss to those without MTRNR1 mutations who have been treated with aminoglycosides, as well as those with MTRNR1 mutations who have not been treated with aminoglycosides. This crucial information will enable the development of an aminoglycoside ototoxicity model to incorporate pharmacogenetic testing into routine pediatric clinical practice. Future studies of this pharmacogenetic model will address the multiple pediatric-specific parameters of pharmacogenetics, including prenatal testing, nonpharmacogenetic implications, extrapolation of test results to other family members, and practical aspects, such as incorporating this information into the patient's medical record for future use. The second aim begins to fill the gap in knowledge regarding parental expectations and perceptions of pharmacogenetic use in pediatric clinical care. Limited information is available regarding patient attitudes toward pharmacogenetic testing in healthy populations, particularly in the pediatric setting. Results from this work will guide the methods for introducin this aminoglycoside pharmacogenetics model into the clinical setting. PUBLIC HEALTH RELEVANCE: Pharmacogenetics has the potential to revolutionize medicine by increasing the efficiency of medication use and avoiding adverse events. Although opportunities for this model are increasing in internal medicine and its subspecialties, the transition to pediatrics has been lagging. This proposal aims to develop the MTRNR1 aminoglycoside induced hearing loss model to facilitate further study of incorporating pharmacogenetics into pediatric clinical practice.